Annual Report HS02243-01 [unreadable] The ability to sense energy level is crucial for responding to metabolic stress such as energy deprivation. In eukaryotic cells, 5 AMP-activated kinase (AMPK), which maintains energy homeostasis by directly sensing the AMP/ATP ratio is an important energy sensor. AMPK plays a central role in food intake and energy metabolism through its activities in CNS and peripheral tissues. Since food intake and energy metabolism is synchronized to the light-dark (LD) cycle of the environment, we investigated the possibility that AMPK may affect circadian rhythm. We discovered that the circadian period of Rat-1 fibroblasts treated with metformin was shortened by 1 hr. One of the regulators of the period length is casein kinase I&#949; (CKI&#949;), which by phosphorylating and inducing the degradation of the circadian clock component mPer2, shortens the period length. AMPK phosphorylates Ser 389 of CKI&#949;, resulting in increased CKI&#949; activity and degradation of mPer2. In peripheral tissues, injection of AMPK activator metformin leads to mPer2 degradation and a phase advance in the circadian expression pattern of clock genes in wild-type mice but not in AMPK &#945;2 knockout mice. We conclude that AMPK has a previously unrecognized role in regulating the circadian rhythm.